Implantable ultrasound generating treating device for spinal cord and/or spinal nerve treatment, apparatus comprising such device and method

ABSTRACT

An implantable ultrasound generating treating device (12) to induce spinal cord or spinal nerves treatment, suitable for implantation in the spinal canal and comprises an elongate support member (22, 32) and an array of several treatment transducers (20) distributed along the elongate support member. The several treatment transducers (20) comprise radial transducers emitting an ultrasound treatment beam oriented radially, wherein the treatment transducers (20) have a resonant frequency comprised between 0.5 and 4 MHz. The device has articulating portions so that the implantable device can adapt its shape to a curved elongation path. Also disclosed is an apparatus including the implantable ultrasound generating treating device and methods comprising inserting the implantable ultrasound generating treating device (12) inside the spinal canal of the spine of the patient.

This application is a Continuation of U.S. Ser. No. 16/082,554 filed onSep. 6, 2018, which is a national phase of PCT/IB2016/000430 filed onMar. 11, 2016.

TECHNICAL FIELD

The present invention relates to a device, an apparatus and a method forthe treatment of spinal cord and or spinal nerve(s) disorders,especially for the transient disruption of the blood-spinal cord barrierand/or of the blood-spinal nerve barrier of a vertebrate subject,especially of a human.

BACKGROUND ART

The spinal cord and/or the spinal nerve(s) may to subject to variousphysiological disorders which induce different forms of pathologiesThere is a clear need for improving therapies in this domain. Also,there is a need to improve the repair and/or rehabilitation treatmentsof the spinal cord and/or spinal nerve(s), for example for hemiplegiaand paraplegia, including with cell transplant and/or stem cellregeneration.

Some available treatments include action of drugs on the spinal cordand/or spinal nerve tissues. However, the blood-spinal cord barrier(hereinafter BSCB) limits or prevents the penetration of therapeuticdrugs in the spinal cord or nerve tissues. Similarly, the blood-spinalnerve barrier (hereinafter BSNB) prevents the penetration of therapeuticdrugs in the spinal cord or nerve tissues.

It is known to use spinal drug delivery catheters inserted in the spinalcanal, but this only allows injection of a fluid which only penetratesto a limited and insufficient extent into spinal cord or spinal nervetissues.

Some documents suggest the use of spinal cord electrical stimulation,sometimes in association with drug delivery. U.S. Pat. No. 6,319,241describes techniques for positioning therapy delivery elements within aspinal cord or a brain to provide electrical stimulation and/or druginfusion to a precise target. U.S. Pat. No. 6,862,479 describesimplantable system control units (SCU) to apply one or more stimulatingdrugs and/or electrical pulses to a spinal section responsible forinnervating the male reproductive organs. Such methods do not cause anysignificant opening of the blood spinal cord barrier.

WO-96/39079 describes a method and an apparatus for performingultrasonic imaging of a region of a patient while simultaneouslyapplying therapeutic ultrasonic waves to the region for rupturingvesicles administered to that region, for purposes such as enhancedcavitation or the targeted release of a bioactive agent contained in thevesicles into the region.

Many systems and methods have been disclosed which rely on high energyultrasounds for causing an intended damage to the targeted tissue.US-2005/0240170 describes methods and systems for producing hemostasis,tissue closure, or vessel closure by inserting a thermal delivery probeinto a passageway and emitting thermal energy from the probe to producethe hemostasis or tissue closure. The thermal delivery probe may haveone or more ultrasound transducers positioned in an elongated shaft.GR20070100349 discloses an ultrasound diathermy system that can beapplied to the spinal cord. It causes a cut and hemostasis in thetissues, it seals vessels of relatively small transection withoutcausing their rupture.

US-2008/0287837 discloses an interstitial end effector which isinterstitially insertable into patient tissue, which includes at leastone medical-treatment ultrasound transducer, and which includes at leastone end-effector-tissue-track ablation device. US-2007/073135, describesan integrated ultrasound imaging and ablation probe. EP-1774989discloses an ultrasound probe which comprises one or more transducerspositionable on, in proximity to or within a cancerous mass of tissue.The one or more transducers are capable of delivering sufficient levelsof acoustic energy to (a) induce coagulative necrosis of a region of thetissue surrounding the transducer, and (b) induce sonoporation of achemotherapy agent into cancer cells in the tumor and in the margins oftissue adjacent the necrosis region of tissue. EP-0643982 describes anultrasound thermotherapy probe and method for treatment of prostatetissues. WO-2007/124458 describes a method of thermal treatment formyolysis and destruction of benign uterine tumors. JP-2007-289715describes an ultrasonic diagnostic and therapeutic system in which highdensity ultrasonic energy can be concentrated and accurately irradiatedon a desired position of a location to be treated.

WO-03/059437 describes a system and method for providing directionalultrasound therapy to skeletal joints, such as spinal joints.WO-03061756 describes a long-term implantable ultrasound therapy systemand method is provided that provides directional, focused ultrasound tolocalized regions of tissue within body joints, such as spinal joints.US-2016/0016012 discloses an external stimulation apparatus using lowintensity focused ultrasound, which has a low intensity ultrasoundfocusing array having a plurality of transducers for outputting lowintensity ultrasound beams, and a fixing device to which the lowintensity ultrasound focusing array is attached, the fixing device beingconfigured to fix the low intensity ultrasound focusing array to anupper body of a user.

US-2015/0224345 discloses a method of treating a patient having a nerveinjury or spinal cord injury or spinal cord lesions, comprising thesteps of: activating an acoustic shock wave generator or source to emitacoustic shock waves from a shock wave head; and administering aneffective exposure of acoustic shock waves in a pulse or wave patternhaving a low energy density less than 1.0 mJ/mm2 per shock wave directlyonto a treatment zone in a region extending from the medulla oblongatain the lower brain stem to the lower end of the spinal cord.

US-2005/0020945 discloses an apparatus including an emitter means todeliver acoustic, ultrasonic or vibratory energy in, into or from withina region of the patient's brain or spine which contains or istransportably-coupled to cerebrospinal fluid (CSF) or blood capable ofbearing or bearing a chemical or biological species, reactant, fragmentor byproduct of the disease.

U.S. Pat. No. 8,942,781 describes a percutaneous probe, made inMRI-compatible materials, having: a body percutaneously inserted intothe tissue of a patient's body organ having a region to be analyzed,treated and monitored during a single medical procedure; at least oneinformation collection sensing device, treatment application transducersorganized in a 360° fashion to emit focused or defocused therapeuticultra-sound waves.

U.S. Pat. No. 8,977,361 describes an apparatus for the treatment of abrain affection, which comprises at least one implantable generator madeof non-ferromagnetic material comprising a casing, and an ultrasoundgenerating treating device positioned into said casing to induce brainaffection treatment by emission of ultrasound waves.

US-2015/0231417 discloses a method for treating a spine comprising thesteps of: providing a magnetic resonance imaging (MRI) device;identifying a surgical site for treatment of a spinal disorder with theMRI device, the surgical site including a portion of a spine; providinga high intensity focused ultrasound (HIFU) device including a transducerfor emitting ultrasound energy; determining parameters of treatment forthe surgical site; and applying a dosage of ultrasound energy to thesurgical site with the HIFU device for treating the disorder.

US-2013/0178765, US-2013/0281890 and US-2016/0001096 describe methodsand systems for non-invasive neuromodulation of the spinal cordutilizing a transducer to deliver pulsed ultrasound energy to upregulate or down regulate neural targets for the treatment of pain andother disease conditions.

There remains the need for a system and a method capable of causing thetransient disruption of the blood-spinal cord barrier and/or of theblood-spinal nerve barrier of a vertebrate subject. The specificity ofthese tissues and their location within the spine vertebrae, especiallyin the spinal canal, and the need to cause only a transient disruptionof the blood-spinal cord barrier and/or of the blood-spinal nervebarrier in the targeted tissues, without damaging the targeted tissues,require a specific system and a specific method not yet available fromthe prior art.

SUMMARY

The invention relates to an implantable ultrasound generating treatingdevice to induce spinal cord or spinal nerves treatment by emission ofultrasound waves, wherein the ultrasound generating treating device issuitable for implantation in the spinal canal and comprises:

-   -   an elongate support member extending along an elongation path;    -   an array of several ultrasound generating treatment transducers        distributed along the elongate support member along an active        portion on the elongation path

The several treatment transducers comprise preferably radialtransducers, each radial treatment transducer emitting an ultrasoundtreatment beam oriented radially with respect to the elongation pathover an effective angular range of at least 120°, preferably at least180°, and most preferably of 360° around the elongation path at thelocation of the radial transducer.

The treatment transducers preferably have an ultrasound generatingresonant frequency comprised between 0.5 and 4 MHz

The implantable device preferably has articulating portions along theactive portion of the elongation path so that the active portion of theimplantable device can adapt its shape to a curved elongation path.

According to other optional features of such implantable device, takenalone or in combination:

-   -   The articulating portions may comprise comparatively more        flexible portions of the device in between of comparatively more        rigid portions.    -   The comparatively more rigid portions may correspond to the        location of the treatment transducers along the elongation path.    -   The device may comprise an elongate outer sheath tube,        containing the ultrasound generating treatment transducers.    -   The elongate outer sheath tube may be made of a silicone,        polyurethane, and/or polytetrafluorethylene based material.    -   The elongate outer sheath tube may form at least part of the        elongate support member.    -   The radial treatment ultrasound generating transducers may be        cylindrical, with an axis parallel to the elongation path.    -   The radial treatment transducers may be tubular, with an axis        parallel to the elongation path, and with a central aperture        extending along their axis.    -   The elongate support member may comprise an internal support        member extending though the central aperture of the treatment        transducers.    -   The ultrasound generating treating device may comprise        ultrasonic monitoring transducers.    -   The treatment transducers may be connectable by an electrical        connection circuit to a generator delivering electric drive        signals driving the generation of ultrasound from the treatment        transducers.    -   The electrical connection circuit of the implantable device may        start from an implantable connection receiver of the implantable        device and may deliver electric signals to the treatment        transducers for driving the ultrasound generation of the        treatment transducers.    -   The connection receiver may be designed for cooperation with an        external electrical generator to achieve electrical connection        between the generator and the ultrasound generating treating        device.    -   The connection receiver may be designed for cooperation with a        connector of the generator which may comprise one or several        transdermal needles suitable for plugging into the connection        receiver through the patient's skin.    -   The device may comprise an implantable electrical generator.    -   The implantable generator may be remotely controlled by an        external controller.

The invention also relates to an apparatus to induce spinal cord orspinal nerves treatment by emission of ultrasound waves, comprising:

-   -   an implantable ultrasound generating treating device having any        of the preceding features;    -   an electrical generator which generates electric signals to be        delivered to the transducers of the implantable ultrasound        generating treating device;    -   a controller.

The invention also relates to a method for transiently opening theblood-spinal cord barrier and/or blood-spinal nerve barrier in at leastone treatment zone of the spinal cord or spinal nerve(s) of a vertebratepatient, especially of a human patient, said method comprising theapplication to the treatment zone of the spinal cord and/or spinalnerve(s) of the patient of at least one ultrasound treatment beam,wherein the method comprises the insertion of an implantable ultrasoundgenerating treating device) inside the spinal canal of the spine of thepatient and the generation of least one ultrasound treatment beam.

According to other optional features of such method, taken alone or incombination:

-   -   The implantable ultrasound generating treating device may be        implanted in the subdural and/or in the epidural space of the        spinal canal.    -   The treatment zone may extends throughout the extension of        several vertebrae of the patient, and the method may comprise        the insertion of an elongate implantable ultrasound generating        treating device inside the spinal canal of the spine and the        generation of least one ultrasound treatment beam.    -   The method may involve the injection of an ultrasound contrast        agent in the patient's blood circulation system, prior to and/or        during the generation of the least one ultrasound treatment        beam.    -   The ultrasound treatment beam may have a resonant frequency        ranging from 0.5 to 4 MHz, preferably ranging from 035 to 2 MHz.    -   The pressure level of the ultrasound treatment beam may be        comprised between 0.8 Mpa and 3.0 Mpa.    -   The applied ultrasound treatment beam may have a mechanical        index (MI) of approximately from 0.3 to 3.00.    -   The ultrasound treatment beam may be a pulsed beam.    -   The implantable ultrasound generating treating device may have        one or several of the features above.

BRIEF DESCRIPTION OF THE DRAWINGS

The device, apparatus and method of the present invention will befurther described in detail below with reference to the accompanyingdrawings showing preferred embodiments of the apparatus of theinvention.

In the Figures:

FIG. 1 represents schematically a first embodiment of the apparatus ofthe present invention;

FIGS. 2 and 3 represent schematically an example of the implantation ofa device according to the invention in the spinal canal of patient,respectively in a sagittal plane and in a transversal plane of thepatient;

FIG. 4 represents schematically a cross section of the implantabledevice, along a plane perpendicular to the elongation path, through atreatment transducer, showing the radial propagation directions of theultrasound treatment beam.

FIG. 5 represents schematically a variant of an implantable ultrasoundgenerating device of the present invention.

DETAILED DESCRIPTION

On FIG. 1 are shown the main components of an apparatus to induce spinalcord or spinal nerves treatment by emission of ultrasound waves,comprising an exemplary embodiment of an implantable ultrasoundgenerating treating device 12 according to the invention.

The apparatus comprises:

-   -   an implantable ultrasound generating treating device 12;    -   an electrical generator 10 which generates electric signals to        be delivered to the transducers of the implantable ultrasound        generating treating device;    -   a controller 15 to set and control the working parameters of the        generator.

According to an aspect of the invention, the implantable ultrasoundgenerating treating device 12 is suitable for implantation inside thespinal canal of the spine of a patient who is awaiting the receipt of,or is receiving medical care or was/is/will be the object of a medicalprocedure, or is monitored for the diagnosis or the development of adisease. The patient can be any vertebrate subject, especially a mammaland in particular a human i.e., a person of the species Homo sapiens.

FIGS. 2 and 3 illustrate schematically such an implantation in the caseof a human patient. On those figures, one can see the spine SN of thepatient, on the internal side of the skin SK of the back of the patient.The spine SN comprises vertebrae V. In a typical human vertebra, asshown on FIG. 3 in a transverse cross-section perpendicular to theextension of the spine, a vertebra comprises a spinal canal SC portionwhich is delimited:

-   -   towards the front by the vertebra body B,    -   towards the sides by the two pedicles P which join the body B to        the two transverse process TP, and    -   towards the rear by the spinous process SP and the two laminas L        which join each the spinal process SP to one of the two        transverse processes TP.

The spinal cord C is located in the spinal canal and the spinal nerves(not represented) emerge from the spinal cord and extend laterally outof the spinal canal between two vertebrae.

More particularly, the implantable ultrasound generating treating device12 is suitable for implantation in the subdural and/or in the epiduralspace of the spinal canal.

In some embodiments, the generator 10 can be implantable inside the bodyof the patient. Such an implantable generator can be remotely controlledby an external controller, preferably through wireless communication.

In other embodiments, as shown on FIGS. 1 and 2 , the generator 10 isexternal to the body.

In operation, the generator 10 and the implantable ultrasound generatingtreating device 12 are to be connected electrically. Whereas suchelectrical connection could be achieved without contact, such as byinductive coupling, the electrical connection of the shown example is amore conventional cable connection. Such electrical connection could bepermanent. However, in the shown embodiment of the invention, electricalconnection is preferably achieved through a connector device 13 of thegenerator system 10 and a connection receiver 16 of the implantabledevice 12 which can be connected and disconnected. In the shownembodiment, the connector device 13 and the connection receiver 16 maybe physically coupled to achieve electrical connection and may bedecoupled without the need to remove the implantable device 12 from thebody of the patient. In this example, the connection receiver 16 forms asocket of a plug-and-socket connection, while the connector device 13forms the plug of a plug-and-socket connection. The connection receiver16 is thus designed for cooperation with the external electricalgenerator 10 to achieve electrical connection between the generator 10and the ultrasound generating treating device 12.

In the shown embodiment of FIG. 2 , the connection receiver 16 isimplantable. It may be affixed, as shown, onto a vertebra, for exampleon the spinous process or a lamina of the vertebra. The connectionreceiver 16 can thus be located below the skin which covers the spine.

The connector device 13 may thus be connected to generator 10 by a cable18 having a suitable length, for example at least 50 centimetres long,preferably more than one meter.

The implantable ultrasound generating treating device 12 is suitable forimplantation in the spinal canal and comprises:

-   -   an elongate support member 22, 32 extending along an elongation        path 11,    -   an array of several ultrasound generating treatment transducers        20 distributed along the elongate support member 22, 32 along an        active portion of the device on the elongation path 11.

The support member maintains a set distance between the ultrasoundgenerating treatments transducers 20 along the elongation path,preferably preventing both an increase and a decrease of the distancebetween the ultrasound generating treatments transducers 20 along theelongation path. The active portion of the device is the portion of thedevice 12 along which the treatment transducers 20 are arranged.

A support member can be for example in the form of tube, of a column, ofa grid, of a skeleton, etc . . . .

In itself, the support member may have a constant flexibility along itslength, or could have segments of different flexibility.

The support member can comprise several members extending in parallelalong all or part of the active portion, including extending coaxially.In case of multiple parallel members, the members can be connecteddirectly or through the treatment transducers 20.

The support member can comprise several parts along its length, forexample in view of providing a modular construction which can be easilyconstructed to the adequate length along the elongation axis.

As described hereunder, the implantable ultrasound generating treatingdevice 12 may additionally comprise an electrical connection networkwith one or several electrically independent electric connectioncircuits 24.

In the shown embodiment, the implantable ultrasound generating treatingdevice 12 comprises an elongate tube 22 which primarily forms aprotective outer sheath for the transducers. It encapsulates an internalspace of the implantable device in which the transducers are located,preferably in a watertight fashion with respect to the exterior of thetube. The elongate tube is thus preferably closed at its both ends 21,23 along the elongation path 11.

In use, the elongate tube 22 is meant to be in contact with body fluidsand tissues of the patient, so it is preferably made of biocompatiblematerial, such as a silicone, polyurethane, and/orpolytetrafluorethylene based material. The elongate tube 22 may haveseveral layers of material, possibly of different composition.

The elongate tube 22 is preferably made of one single part, for exampleobtained by extrusion. However, a multi-part construction is alsopossible, for example in view of providing a modular construction whichcan be easily constructed to the adequate length along the elongationaxis.

In some embodiments, as shown on FIG. 1 , the tube 22 may serve also asa support member for the treatment transducers 20, the treatmenttransducers 20 being thus affixed to the elongate tube 22.

The elongate tube 22 in itself may have a constant rigidity along itslength, or could have segments of different rigidity.

However, in some embodiments, as shown on FIG. 5 , the support membercould comprise a distinct support member 32, distinct from a tubularouter protective sheath, the treatment transducers 20 being thus affixedto the distinct support member 32.

As shown on FIG. 5 , in those embodiments having a support member 32distinct from an outer protective sheath, which may be formed by anelongate tube 22 as described above, the outer protective sheath mayalso have a role of supporting the treatment transducers 20, in whichcase the support member can comprise both a distinct support member 32and an outer protective sheath such as the elongate tube 22.

The several ultrasound treatment transducers 22 comprise radialtransducers, each radial treatment transducer emitting an ultrasoundbeam oriented radially with respect to the elongation path 11, i.e.perpendicularly to the elongation path, over an effective angular rangeof at least 120°, preferably over 180° and more preferably over 360°around the elongation path at the location of the radial transducer.

Preferably, the ultrasound treatment beam delivered by a given radialtreatment transducer 20 has propagation directions contained in a planewhich is perpendicular to the elongation axis at the location of thetransducer 20 or which deviate from this plane by an angle less than45°, preferably less than 30°, considering only those propagationdirections for which acoustic pressure of the ultrasound field is equalto at least a certain percentage, for example 25%, of the acousticpressure at the same distance from the elongation axis along a directionof maximum acoustic pressure.

The effective angular range of the radially oriented ultrasound beam isthe angle, in a plane perpendicular to the elongation path at thelocation of the radial transducer, containing the propagation directionsfor which acoustic pressure of the ultrasound field is equal to at leasta certain percentage, for example 25%, preferably at least 50%, morepreferably at least 75% of the acoustic pressure along a direction ofmaximum acoustic pressure in that plane.

Preferably, the effective angular range is a continuous range.

Thus, in a plane perpendicular to the elongation path at the location ofthe radial transducer, the acoustic power is not necessarily constant inall directions around the elongation axis contained in the effectiveangular range. However, the acoustic pressure delivered in the effectiveangular range is considered sufficient in all directions of theeffective angular range to achieve the desired therapeutic effect oftransiently opening the BSCB or BSNB.

The radial treatment ultrasound generating transducers may becylindrical, with an axis parallel to the elongation path 11.

The radial ultrasound treatment transducers may be tubular, with an axisparallel to the elongation path 11, and with a central apertureextending along their axis. In such a case the elongate support membermay, as shown in FIG. 5 , comprise an internal support member extendingthrough the central aperture of the ultrasound treatment transducers.However, even in the case of tubular ultrasound treatment transducers,the support member may be external to the ultrasound treatmenttransducers. In both cases, the central aperture of the transducers maystill serve as a pathway for the electrical connection circuit 24.

Cylindrical or tubular radial transducers could exhibit a cross sectionwhere the outer surface, i.e. the ultrasound emitting surface, is in theshape of, or aligned along a line which can be a circle, or a partthereof such as a semi-circle, an ellipse or quasi ellipse or partthereof, a parabola or quasi parabola or part thereof, an hyperbola orquasi hyperbola or part thereof, or any curved or prismatic line, aslong as the emitted ultrasound treatment beam is oriented radially asdefined above.

The elongation axis at the location of transducer can be the axis of thetransducer cylinder.

A radial treatment transducer 20 can be made of a single transducerelement, but is preferably made of several transducer elements which arearranged around the elongation axis along the effective angular range.

In FIG. 4 , it is shown an example where a radial treatment transducer20 has, in a plane perpendicular to the elongation path at the locationof the radial transducer, eight principal directions of propagationalong which the acoustic power reaches locally a maximum level at a samegiven distance from the elongation axis along that direction. Theseeight maximum levels are preferably in the same order of magnitude,preferably not different by more than 25%. These eight principaldirections of propagation are spread over 360°, at regular intervals.Such radial transducer can typically be made of eight transducerelements. Another example could have the same features for moreprincipal directions, for example for at least 10, 15, 20 or 30principal directions. Having an effective angular range of at least120°, preferably over 180°, allows that, if the implantable device 12 iscorrectly installed in the subdural and/or in the epidural space of thespinal canal, the spinal cord will be effectively treated.

Having an effective angular range of 360°, allows that once theimplantable device 12 is installed in the spinal canal, the spinal cordwill be effectively treated no matter what is the effective angularorientation of the implantable device 12 around its axis.

A radial treatment transducer 20 may have a longitudinal extension,along the direction of the elongation path, which may be comprisedbetween 1 and 20 mm, preferably comprised between 3 and 10 mm.

The ultrasound generating treatment transducers 20 are preferably choseninto the group formed by piezo-composite elements, piezo-ceramicelements, CMUT elements (Capacitive micro-machined ultrasonictransducers), or PVDF elements (Poly(vinylidene fluoride)).Piezo-composite elements or piezo-ceramic elements usually have a sizein the range of 1 to 50 mm in diameter. CMUT elements usually have asize in the range of 10 to 50 μm in diameter. Piezoelectric componentsare commonly used in the medical field as ultrasound transducers. Agiven transducer can comprise one or several discrete elements which areactivated simultaneously.

Preferably, the treatment transducers generate unfocused ultrasounds.

The ultrasound treatment transducers have an ultrasound generatingresonant frequency comprised between 0.5 and 4 MHz, more preferablybetween 0.75 and 2 MHz, for achieving transient disruption of theblood-spinal cord barrier and/or of the blood-spinal nerve barrier ofthe targeted portion of the spinal cord and/spinal nerve(s).

In most commonly used ultrasound generating transducers 20, theultrasound energy is generated by virtue of the vibration created in thecore of the transducer by an alternating voltage by virtue of apiezoelectric effect or capacitive variation. The transducer is fed withan electric voltage which may have a given frequency or which may have afrequency spectrum which may be decomposed into preferably a limitednumber of main frequencies. The core of the transducer may thus bedesigned such that it exhibits at least one inherent resonant frequency.

A resonant frequency of the transducer can be defined as the frequencyof the drive signal for which the ratio of the acoustic power outputdivided by consumed electrical power reaches a maximum (at least withinneighbouring frequencies). For a typical piezoceramic transducer, thisratio is typically between 50% and 90% at a resonant frequency. If theelectric current fed to the transducer exhibits such frequency, it willinduce in the transducer a resonant vibration which will generateultrasound. If the electric current fed to the transducer exhibits onlya frequency or frequencies which lie outside of a resonant range aroundthe resonant frequency, then the acoustic power output will be less than25% of the power delivered when driven with a given voltage at itsresonant frequency.

It must be noted that the term resonant frequency, as used in this text,covers an individual peak resonant frequency, at which the transducer 20delivers a peak ultrasound field power/intensity for a given electricdrive signal power, or a resonant frequency range, around such peakresonant frequency, for which the transducer 20 delivers a ultrasoundfield power/intensity higher than a minimum field power/intensity, whichmay be expressed as a percentage of the peak ultrasound fieldpower/intensity.

A transducer may have a given operating frequency by choosing forexample its resonant thickness along a given direction along which theultrasound waves are to be emitted. For example, thickness for a 1 MHztransducer for PZ26 material should be at 2 mm along the radialdirection, or thickness for a 4 MHz transducer for PZ26 material shouldbe at 0.5 mm along the radial direction.

The frequency content of the electric drive signal can be obtaineddirectly, in case of a simple alternating voltage having one frequency,such as a pure sinusoidal signal. It can also be obtained through FastFourier Transform (FFT), as known to the man skilled in the art ofsignal processing.

It can be noted that, the intensity/power of the ultrasound fieldgenerated by a given transducer will depend on the amplitude of theelectric drive signal delivered by the generator 10 at the operatingfrequency.

The implantable device 12 has articulating portions along the activeportion on the elongation path 11, so that it can deform, i.e. adapt itsshape, to a curved elongation path 11.

As whole, the implantable device 12 is thus flexible along at least partof the length of its active portion in order to be insertable in thespinal canal. This involves following the curved shape of the spinalcanal along the elongation of the spine. This also involves allowing theinsertion of the implantable device 12 through a primary access vertebrafrom an opening.

Indeed the implantation of the implantable device 12 is to be performedeither by a surgical process, involving a surgical opening, or by apercutaneous process, involving a much smaller percutaneous opening. Inboth cases, the opening is preferably practiced in the spine region ofthe back of the patient. A distal end 21 of the device, here of theelongate tube 22, is introduced though the surgical or percutaneousopening and is guided towards the spinal canal portion of the primaryaccess vertebra, passing between said vertebra and a proximal vertebra,for example between respective laminas of the two vertebras. The distalend 21 of the implantable device 12 is then guided along the spinalcanal, in the subdural and/or in the epidural space, for examplefollowing a front or rear surface of the spinal cord.

The insertion process can be performed blindly, but it is preferablymonitored by known imaging techniques, including X-Ray or ultrasoundimaging techniques, including by endoscopy.

The flexibility of the device 12 along its elongation path 11, at leastalong its active portion, should allow this insertion and this abilityto follow the shape of the spinal canal. The skilled practitioner willbe able to determine the required flexibility to avoid any damage to thetissues, especially to the spinal cord and especially during theinsertion process.

According to a desirable feature deriving from that flexibility, theimplantable device 12 as a whole, including its elongate support member22, 32, its transducers and its electrical connection circuits(s) in theactive portion, is preferably at least manually deformable between atleast a first spatial configuration, or shape, to at least a secondspatial configuration or shape, meaning that, before its implantation orduring its implantation, the implantable device 12 may be deformed to adesired shape by the mere application of biasing or deformation forceswhich are comparable to those which may be easily applied by hand.Typically, for an implantable device 12 to be considered as flexible, asurgeon implanting such device should be able to deform the implantabledevice 12 to give it a certain spatial configuration without resort toany kind of tool. This does not prevent however that deformation and/orimplantation of the implantable device 12 can be deformed/implantedusing tools typically employed in surgery, especially tools forperforming remote-control surgery.

Preferably, the implantable device 12 is reversibly deformable suchthat, after it has been deformed from a first spatial configuration to asecond spatial configuration, it can be deformed back to its firstspatial configuration or very near to such spatial configuration.

The amount of manual reversible deformation possible for a givenimplantable device may be evaluated as a curvature radius of theelongation path. Preferably, the implantable device is reversiblydeformable such that its elongation path may exhibit, along the activeportion of the device and after reversible deformation, a radius ofcurvature of less than 15 cm, preferably less than 10 cm.

The implantable device 12 as a whole, including its elongate supportmember 22, 32, its transducers and its electrical connection circuits(s)in the active portion, has preferably a low degree of elasticity. If theimplantable device is deformed from an initial spatial configuration toa temporary spatial configuration upon application of a biasing ordeformation force, it may attain a final spatial configuration, due to aspring back effect, upon release of the biasing or deformation force.Low elasticity can be assumed if the difference of radius of curvatureof the final spatial configuration compared to the temporary spatialconfiguration (i.e. due to the spring back effect) is for example lessthan one fourth of the radius of curvature of the temporary spatialconfiguration, preferably less than one the tenth.

Preferably, the implantable device 12 as a whole, including its elongatesupport member 22, 32, its transducers and its electrical connectioncircuits(s) in the active portion, may be ultra-flexible, i.e.exhibiting a very low degree of rigidity. Such implantable device 12cannot hold its own weight. For example, an implantable device 12 willbe considered ultra-flexible if, along at least one test direction, whenthe implantable device 12 is clamped at one extremity of the activeportion of the implantable device 12 so that the clamped extremityextends substantially horizontally, the implantable device 12 exhibits,by virtue of its sole weight, a radius of curvature of less than 15 cmalong its active portion. Such an ultra-flexible implantable device 12will have the advantage of generating the least possible pressure on thetissues which may be due to its deformation. Such ultra-flexibleimplantable device 12 may also be defined by the fact that itautomatically adopts the shape of a surface it is in contact with,without generating any pressure, or at least without generating anysubstantial pressure, which pressure would be due to its own elasticityor rigidity. Of course, it may generate some pressure, for example dueto its weight, and/or due to its thickness if sandwiched between twosurfaces.

In some embodiments, one, several or all the articulating portions maycomprise mechanical articulating portions comprising two rigid partshaving a relative motion along respective sliding surfaces, such as apivot or ball joint connection. For example, the support member maycomprise a skeleton having successive rigid segments articulated one tothe other by mechanical articulations.

An articulating portion may have three rotational degrees of freedom, asin a spherical ball joint.

An articulating portion may have two rotational degrees of freedom, ormay have two preferred rotational degrees of freedom, for example aroundtwo axes perpendicular to the elongation axis with more limitedflexibility or no rotational freedom of rotation along the thirdperpendicular axis, for example along the elongation axis.

However, an articulating portion may have only one rotational degree offreedom, or have one preferred rotational degree of freedom for examplearound an axis perpendicular to the elongation axis, with more limitedor no rotational freedom of rotation along the elongation axis and alongthe other perpendicular axis.

A preferred rotational degrees of freedom is one for which thearticulating portion of the device shows greater flexibility than fornon-preferred rotational degrees of freedom.

As a whole, by proper choice of preferred rotational degree(s) offreedom of its successive articulating portions, an implantable devicemay exhibit a preferred plane of deformation, where the implantabledevice, as a whole, will exhibit greater flexibility along its activeportion than for a non-preferred plane of deformation.

In all cases, an articulating portion may have a limited angular rangeof articulation for a one or several of its rotational degree offreedom. A limited angular range of articulation for one of itsrotational degree of freedom may be different than a limited angularrange of articulation for another rotational degree of freedom of a samearticulating portion.

However, as shown in the depicted embodiment, an articulating portion ofthe device preferably comprises a flexible deformation portion 25. Suchflexible deformation portions 25 are preferably part of the supportmember(s) which support the transducers. Typically, the flexibledeformation portions 25 are part of support member 22, 32, i.e. of thedistinct support member 22 and for of the elongate tube 22.

In some embodiment, the implantable device 12 as a whole may exhibit aconstant flexibility, at least along its active portion, or partthereof. In such a case, the articulating portions form a continuousarticulating portion along the length of the implantable device 12, orat least along the length of its active portion, or part thereof.

In the example shown, articulating portions 25 are located along theelongation path between treatment transducers 22 along the elongationpath 11.

The articulating portions may be formed of comparatively more flexibleportions 25 of the device 12, in between of comparatively more rigidportions 27.

The comparatively more rigid portions 27 may correspond to the locationof the treatment transducers 22 along the elongation path 11. Indeed,most ultrasonic treatment transducers 20 comprise a rigid core whichgenerates the vibration. In an embodiment where the support member 22,32 for the transducers is formed of a flexible material, such rigidtransducers will impart a relatively high degree of rigidity to thecorresponding portion of the device.

Accordingly, especially in such cases, it is preferable to provide acertain distance between two successive treatment transducers 20 alongthe elongation path 11. Such distance is for example superior to 5 mm,preferably superior to 10 mm.

Thus, a portion of the device, extending between two successivetreatment transducers along the elongation path 11, may form anarticulating portion 25, where the articulation is formed thanks to theflexible deformation of the support member 22, 32 along such portion.

This can also be provided when the support member 22, 32 comprises rigidsegments which are articulated between each other, as this avoidsmechanical interference between successive treatment transducers 20 uponcurving of the shape of the implantable device.

Such distance between two treatment transducers 20 also limits the riskof the ultrasound waves generated by two successive transducersoverlapping in the treatment zone. Such overlapping could indeed lead toundesired peak ultrasound power in the overlapping zone.

It can be noted that the support member 22, 32, on which the treatmenttransducers are affixed, remains in place within the implantableultrasound generating device 12 when the latter is used, i.e. duringapplication of the ultrasound treatment beam by activation of theultrasound generating treatment transducers 20. This does not preventthat a removable mandrel may be used in connection with the implantableultrasound generating device 12, especially during insertion of thedevice in the body of the patient. Such removable mandrel may comprisean inner mandrel which may be temporarily received within theimplantable ultrasound generating device 12.

The implantable ultrasound generating treating device 12 may compriseultrasonic monitoring transducers, for example wideband ultrasonictransducers. Monitoring transducers may comprise flexible membranetransducers. Monitoring transducers are preferably able to pick-up anultrasound signal over a wide frequency range, ideally between 50 kHzand 50 MHz. Such monitoring transducers may be tailored and used formonitoring cavitation due to the ultrasonic treatment. The ultrasonicmonitoring transducers may be held by the same support member as thetreatment transducers, for example the elongate tube 22, or by aseparate support member. One or several ultrasonic monitoringtransducers may be located in between two treatment transducers.

The implantable ultrasound generating treating device 12 also comprisesan electrical connection network for connecting the ultrasoundgenerating transducers 20 to the generator 10 delivering electric drivesignals. In the shown embodiment, the electrical connection networkstarts from the connection receiver 16 and delivers electric signals tothe transducers for driving the ultrasound generation of thetransducers. In some embodiments, an electric drive signal may serveboth as power signal and as a control signal. The electric connectionnetwork may comprise one or several electrically independent electricconnection circuits 24, where it will be understood that a givenelectric connection circuit 24 is a circuit where a common electricdrive signal is circulating.

In some embodiments the electric connection network may comprise onlyone independent electric connection circuit 24 for the treatmenttransducers, so that the electric connection between implantableultrasound generating device 12 and the generator, here through theconnector 13 and the connection receiver 16, can be made as simple aspossible. Indeed, in such a case, only one two-way connection will beneeded for connecting the treatment transducers, with one electricalchannel for the signal connection and one electrical channel for theground return. Such a single electric connection circuit implies thatall treatment transducers are driven by a single electric drive signal.

However, the electric connection network may comprise severalindependent electric connection circuits. An independent electricconnection circuit may be used to drive a single treatment transducer ormay be used to drive a group of treatment transducers. Each independentelectric connection circuit will have its own independent electricconnection to the generator 10 and the generator may deliver separateand different electric drive signals to each independent electricconnection circuit. Independent electric connection circuit may beuseful for addressing possible impedance variation between transducers.

In any case, monitoring transducers, if present, would preferably havetheir own separate electric connection circuit.

In the shown example, although it is implantable, the connectionreceiver 16 is separate from the elongate tube 22. Therefore, theelectric connection circuit 24 comprises at least one cable 26, mostcommonly made of at least one pair of wires where one wire correspondsto one independent electrical channel, which extends outwardly from aproximal end 23 of the the elongate tube 22 to the connection receiver16. Preferably, there is a single cable 26, although it may compriseseveral electrically separate wires bundled together. Inside theelongate tube 22, the cable 26 of electric connection circuit 24 mayseparate into connection lines 28 for delivering an electric drivesignal to the individual transducers 20 of a given group of transducers.

The implantable device 12 may have, in cross section perpendicularly toits elongation axis, a shape where the outer surface, for example theouter surface of an outer protective sheath, is in the shape of, oraligned along a line which can be a circle or a part thereof such as asemi-circle, an ellipse or quasi ellipse or part thereof, a parabola orquasi parabola or part thereof, an hyperbola or quasi hyperbola or partthereof, or any curved or prismatic line. The shape of the implantabledevice 12 in cross section might be identical to that of the radialtreatment transducers 20, or not.

Preferably, the implantable device 12, thus here the elongate tube 22,has a maximum transverse dimension perpendicular to its elongation path,for example its external diameter in the case of device of circularcross section, which is less than 6 mm, preferably less than 4 mm.

Preferably, the implantable ultrasound generating treating device 12 ismade of non-ferromagnetic material, preferably MRI compatible material.

When designed to be connected to an external generator, the implantableultrasound treating device 12 may be designed with an external, i.e.non-implantable, connection receiver 16.

In the case of an implantable connection receiver 16, the connectionreceiver 16 may have a casing, for example a rigid casing, which may befastened to a vertebra by any suitable means, such as bone screws.

For example, one or several connecting plugs may be located within theimplantable casing and may be adapted to physically connect with one orseveral connecting needle(s) 14 from the generator systems. A connectingneedle 14 is preferably a transdermal needle. Such needles are suitablefor piercing the patient's skin and plugging into the connecting plugsinside the implantable casing, preferably through a wall of the casingwhich can be advantageously made of, or comprise a portion made of, anisolating concealable material like Silastic®, from the siliconemanufacturer Dow Corning. This material can easily and automaticallyreseal when the needle 14 is withdrawn from the implantable connectionreceiver 16. Advantageously, the transdermal needle 14 may be coatedwith an isolating material, for instance wax or plastic, on its entirelength except at its tip so that an electric contact can be establishedat its tip with a connecting plug inside the connection receiver totransfer electric current to the implantable connection receiver 16without causing burning of the patient's skin. An embodiment maycomprise a two-way connection by means of a single transdermal needle 16which carries, on one way, i.e. one electrical channel, the electricdrive signal and, on the other way, the ground connection between thegenerator 10 and the implantable treating device 12, which in this case,has only one independent electric connection circuit 24, thus only onegroup of transducers. Two single-way needles could have been provided,one for the electric drive signal and one for the ground return. Furtherdescription of such connection can be found in U.S. Pat. No. 8,977,361which is hereby incorporated by reference.

However, in case of an implantable ultrasound generating device havingseveral independent electrical connection circuits, an independentconnection for each electrical signal corresponding to each independentelectrical connection circuit would be needed, plus at least one commonground connection. This could be achieved with a single needle havingone way per electrical signal plus one way for the ground return, orwith several needles.

The generator 10 is adapted for delivering electric drive signals to bedelivered to the ultrasound generating treatment transducers 20 of anassociated ultrasound generating treating device 12. The generatortypically comprises an alternating voltage generator able to generate anelectric signal, for example a sinusoidal electric voltage signal. Oneexample of a generator system that can be used with the inventive devicemay include a system that integrates signal generation, amplification,and control into a single unit. However, a generator system can alsocomprise one or several individual components performing one or more ofthese functions. For example, the generator can include an HP/Agilent33120 function generator. If needed, it can also include for example oneor more of an ENI 240 L. Broadband RF amplifier, of a Rhode and SchwarzRE power meter, and/or external computer controlling equipment overGPIB/Serial/USB interfaces.

Therefore, the controller 15 may comprise a computer. A computerhuman/machine interface 17, for example a keyboard, and/or mouse and/ora display and/or a touchscreen interface, can be provided to control thesystem and give the user feedback. A radiofrequency board that generatesthe RF signal and amplifies it may be provided, as well as a coupler tomeasure the delivered RF power, and matching components to tune thegenerator output to the impedance of the ultrasound elements.Preferably, the generator 10 may be of a type capable to deliver 25-100W peak RF power, capable of sending burst lengths with durations of 1microsecond to continuous mode, and capable of sending bursts within thefrequency range of 500 kHz to 2 MHz. Such a system can be controlled tosend pulses with variable frequency and duty cycles for durations ofapproximately 2-5 minutes. The generator may be a class A/B RF system,which means that it is capable of generating nearly pure sinusoidalsignals, but this may make the system rather large. In some embodiments,especially in the case where the generator is implantable, the generatorcould be a class D system, which tends to generate signals that aresquare wave on the output.

The controller 15 may thus comprise a treatment control module forcontrolling the generator of view of providing the adequate electricdrive signals to the implantable ultrasound treating device 12.

The controller 15 may also comprise a monitoring module connected to themonitoring transducers of the implantable ultrasound treating device 12,if provided with such monitoring transducers.

According to another aspect of the invention, it is provided a methodfor transiently opening the blood-spinal cord barrier (BSCB) orblood-spinal nerve barrier (BSNB) in at least one treatment zone of thespinal cord or spinal nerve(s) of a vertebrate patient, especially of ahuman patient.

In the context of the invention, the terms “disrupting”, “opening” or“increasing the permeability” of the BSCB or BSNB are usedinterchangeably to refer to an increased susceptibility of the BSCB orBSNB to the passage of molecules therethrough that occurs withoutdetectable damaging of the spinal cord or spinal nerve tissue.

The method can be used for delivering substances into targeted spinalcord or spinal nerve tissue of the subject and/or for treating a thespinal cord or spinal nerve disease.

The method comprises the application to the treatment zone of the spinalcord of the patient of at least one ultrasound treatment beam.

The terms “ultrasound beam”, “ultrasound wave” and “ultrasound” are usedindifferently for designating sound waves with frequencies higher than20 kHz. However the ultrasound treatment beam has preferably anultrasound frequency ranging from 0.5 to 4 MHz, more preferably ranging0.75 to 2 MHz.

The ultrasound energy may be focused ultrasound or unfocused ultrasoundto treat a large zone of the BSCB or BSNB.

The method comprises the insertion of an implantable ultrasoundgenerating treating device inside the spinal canal of the spine of thepatient and the generation of least one ultrasound treatment beam. Theuse of such an implantable device allows for a very precise control ofthe ultrasound energy and power delivered to the targeted spinal cordand spinal nerve tissues. It also allows a precise targeting of thetreatment zone, with the possibility to precisely control the extensionof such treatment zone where the ultrasound treatment beam iseffectively applied.

Most preferably the implantable ultrasound generating treating device isimplanted in the subdural and/or in the epidural space of the spinalcanal.

The implantable ultrasound generating treating device 12 may bemaintained in the spinal canal of the patient for days, weeks or months.It is then possible to perform repetitive BSCB or BSNB disruptions for along period of time. The implantable ultrasound generating treating maybe activated for each BSCB or BSNB disruption, for instance before eachchemotherapy session of a patient in need thereof.

In the context of the invention, a “transient” opening refers to areversible opening occurring preferably for more than 1 hour, the BSCBor BSNB returning after that to its initial state (i.e., the BSCB orBSNB state before the application of the first ultrasound treatmentbeam).

In some embodiments, the BSCB or BSNB opening occurs for a period oftime from 1 to 48 hours, preferably from 5 to 24 hours, more preferablyfrom 6 to 10 hours. In some embodiments, the BSCB or BSNB opening occursfor approximately 8 hours.

In some embodiments, the BSCB or BSNB disruption is delimited, i.e.,occurs solely in a target region of the BSCB or BSNB. For instance, onlya region of the BSCB or BSNB surrounding damaged spinal cord or spinalnerve tissue, such as a tumor, is targeted. In other embodiments, theBSCB or BSNB disruption is generalized.

The disruption may be easily confirmed and/or evaluated by magneticresonance imaging (MRI). For example, a gadolinium-based magneticresonance (MR) contrast agent such as Dotarem® (gadoterate meglumine,Guerbet USA), which does not normally cross the BSCB or BSNB, can beused to visualize the region of BSCB or BSNB disruption. When the agentis injected in a patient, a T1w MR sequence can be used to visualizeregions of hypersignal and therefore visualize the effect of BSCB orBSNB disruption by ultrasound. BSCB or BSNB disruption typically leadsto a change of 5-10% or more in MR signal enhancement after contrastagent administration. With the invention, a change of more than 25%,preferably more than 50% in MR signal enhancement after contrast agentadministration is contemplated. In addition, dynamic contrast enhanced(DCF) MR imaging techniques can be used to calculate the permeability ofthe BSCB or BSNB and to quantify the magnitude of the permeabilityenhancement after ultrasound treatment.

The treatment zone can be very limited in its extension, for examplecorresponding to the spinal canal portion of a single vertebra. However,the treatment zone may extend throughout the extension of severalvertebrae of the patient. In such a case the method may comprise theinsertion of an elongate implantable ultrasound generating treatingdevice inside the spinal canal of the spine and the generation of leastone ultrasound treatment beam. In the case of an adult human, the lengthof the active portion on an elongate implantable ultrasound generatingtransducer is preferably of at least 10 cm, preferably at least 20 cmand more preferably at least 40 cm

The method preferably involves the injection of an ultrasound contrastagent in the patient's blood circulation system, prior to and/or duringthe generation of the least one ultrasound treatment beam.

The term “ultrasound contrast agent” is used herein to refer to asubstance (solid, liquid or gas) that is able to enhance the contrastbetween the region containing the agent and the surrounding tissue in anultrasound image. Advantageously, the ultrasound contrast agentcorresponds to small bubbles of a gas, termed “microbubbles,” with anaverage diameter between 1 μm and 10 μm. Said microbubbles oscillate andvibrate when a treatment ultrasound beam is applied and may reflectultrasound waves. The ultrasound contrast agent is generally injectedintravenously into the blood stream in the patient's blood circulationsystem, wherein it remains for a limited period of time.

The ultrasound contrast agent may be administered by injection,preferably by systemic injection. Examples of systemic injectionsinclude intravenous, subcutaneous, intramuscular, intradermal, intravitreal and intraperitoneal injection, or perfusion.

Preferably, the ultrasound contrast agent is administered as a bolusjust before the ultrasound treatment beam application. More preferably,the ultrasound contrast agent is administered between 0 and 60 minutesbefore, and/or during the ultrasound treatment beam application. Whensuccessive ultrasound treatment beams are applied, the ultrasoundcontrast agent is preferably delivered only once, just before the firstultrasound treatment beam application of the cycle, though it may bedelivered at activation of each US beam, or by a continuous infusionthrough the activation of successive ultrasound treatment beams.

According to the invention, the ultrasound contrast agent may containgaseous bubbles, a high concentration of gas, solid particles configuredto vaporize in response to ultrasound, liquid configured to vaporize inresponse to ultrasound, micro particles configured to act as cavitationsites, solid particles having higher acoustic impedance than tissue inthe desired region, and/or liquid with a high acoustic absorptioncoefficient.

In some embodiments, the ultrasound contrast agent is a microbubblecontrast agent, preferably selected from the group consisting of sulphurhexafluoride microbubbles (SonoVue®), microbubbles made of an albuminshell and octafluoropropane gas core (Optison®), perflexane microbubblesencapsulated in an outer lipid shell (Imagent®), microbubbles made ofoctafluoropropane gas core encapsulated in an outer lipid shell(Definity®), or perfluorobutaine and nitrogen gas encapsulated in alipid shell (BR38-Schneider et al., 2011). Preferably, the ultrasoundcontrast agent consists of sulphur hexafluoride microbubbles.Microbubbles may contain a drug and/or a nanoparticle which may bedelivered in situ when the microbubbles are exposed to the ultrasoundtreatment beam.

The microbubbles may have a mean diameter in a range from 1 μm to 10 μm.In some embodiments, the microbubbles have a mean diameter in a rangefrom 4 μm to 5 μm. In some other embodiments, the microbubbles have amean diameter in a range from 2 to 6 μm. In some embodiments, themicrobubbles have a mean diameter of approximately 7 μm, 6 μm, 5 μm, 4μm, 3 μm or 2 μm. In a particular embodiment, the microbubbles have amean diameter of approximately 2.5 μm.

In some embodiments, the dose of ultrasound contrast agent rangesbetween 0.05 and 0.15 ml/kg based on the total weight of the subject.Preferably, the dose of ultrasound contrast agent is approximately 0.1ml/kg. In a particular embodiment, the maximum dose of ultrasoundcontrast agent is up to 10 ml.

Preferably, the pressure level of the ultrasound treatment beam appliedto the spinal cord or spinal nerve tissues is comprised between 0.8 MPaand 3.0 MPa. Advantageously, the ultrasound treatment beams are appliedwithin a pressure range of 0.8 MPa to 2.5 MPa, more preferably within apressure range of 0.8 MPa to 2.00, even more preferably within apressure range of 0.8 MPa to 1.9, such as within a pressure range of 0.8MPa to 1.5 MPa, within a pressure range of 1.1 MPa to 1.5 MPa. In aparticular embodiment, the ultrasound treatment beams are applied with apressure level of 1.25 MPa. In another embodiment, the ultrasoundtreatment beams are applied with a pressure level of 1.5 MPa. In afurther embodiment, the ultrasound treatment beams are applied with apressure level of 1.9 MPa. In the context of the invention, the“pressure level” refers to the maximum acoustic pressure measured in theacoustic field of the device in water. It is believed that such pressurelevels may be applied in a safe manner to human's spinal cord and/orspinal nerve, i.e., no detected damages of spinal cord and/or spinalnerve tissue should be observed.

In the context of the invention, the value of the pressure levelcorresponds to the value onto the spinal cord and/or spinal nervetissue. The pressure emitted by the device may differ, to take intoaccount potential attenuation of intervening tissues and/or vertebrabone reverberation. One skilled in the art will be able to adapt thevalue of the pressure level coming out of the emitter to obtain therequired pressure level onto the spinal cord and/or spinal nerve.Monitoring of the treatment zone with ultrasonic monitoring transducerscan be used for checking the effective value of the pressure level insitu during the treatment. Monitoring of the treatment zone withultrasonic monitoring transducers can be used to record emittedultrasound signal (harmonics, sub-harmonic waves, all broad bandemission frequencies waves) from microbubbles during their cavitationinduced by therapeutic transducers. This echo detected signal can allowthe monitoring of inertial or stable cavitation of the microbubbles.

Preferably, the applied ultrasound treatment beam has a mechanical index(MI) of approximately from 0.3 to 3.00, and preferably in the range of1.05 to 1.8 in the case of a 1 MHz ultrasound treatment beam. In thecontext of the invention, the MI refers to the peak negative pressure insitu (MPa) divided by the square root of the frequency (MHz).

Preferably, the ultrasound treatment beam is a pulsed beam. In thecontext of the invention, a “pulse” refers to a continuous burst,without interruption, of sinusoidal waves that may comprises severalcycles.

In some embodiments, the method comprises the application of one or morepulses, or bursts, comprising from 100 to 100,000 successive cycles,preferably from 1,000 to 75,000, more preferably from 10,000 to 50,000,even more preferably from 20,000 to 30,000. In a particular embodiment,the method comprises the application of pulses of 25,000 successivecycles. In some embodiments, the mean burst duration of an ultrasoundtreatment emission (i.e., the mean time from the start of a pulse to theend of that pulse) is between 10 msec. and 100 msec., preferably between15 msec. and 50 msec., more preferably between 20 msec. and 30 msec.,even more preferably approximately 25 msec.

The delay between two successive pulses is preferably from 30 msec. to1000 msec. In a particular embodiment, the delay between two successivepulses is approximately 975 msec.

Advantageously, the successive pulses are applied within a totalduration from 1 to 20 minutes. In a particular embodiment, thesuccessive pulses are applied within a total duration that does notexceed 10 minutes, preferably 5 minutes. In a particular embodiment, thesuccessive pulses are applied within a total duration of 150 seconds.

In a particular embodiment, pulses of 25,000 cycles are applied to thesubject, at a pulse repetition frequency (PRF) of 1 Hz, every 1000 msec.with a pressure level of 1.1 MPa and a burst duration of about 23 msec.for a total duration of 150 seconds.

A treatment transducer has an ultrasound emission zone in which theintensity of the ultrasound field is significant. The ultrasoundemission zone can be defined by a border emission envelope of theemission zone which can itself be defined as the envelope containing alllocations where the acoustic pressure of the ultrasound field is equalto at least a certain percentage, for example 25%, of the acousticpressure at the same distance from the transducer along a direction ofmaximum acoustic pressure. As discussed above, the treatment transducers20 of an implantable device according to the invention are preferablydesigned and arranged along the support member 22, 32 so the emissionzones of two successive treatment transducers along the elongation path11 do not intersect. Providing two successive treatment transducers 20at a certain distance from each other, as described above, for exampleat least 10 mm apart, participates in avoiding such intersection

However, as a complement or an alternative, it can be provided that twosuccessive treatment transducers 20 are not activated simultaneously.

For example, the treatment transducers 20 can be divided in two or moresets of non-consecutive treatment transducers 20 along the elongationpath 11, each set of treatment transducers being activated separately intime, not simultaneously. For example, one can provide two or three setsof transducers 20, where each set is made of one out of every twotreatment transducers 20, respectively one out of every three treatmenttransducers 20, along the elongation path 11.

Each set of treatment transducers, which is to be activated separatelyin time, may be electrically connected to the generator through its ownindependent electrical connection circuit.

The method according to the invention is preferably implemented with theuse of an implantable ultrasound generating treating device as describedabove, and preferably with a treatment apparatus comprising such adevice.

The devices, apparatus and methods according to the invention can beused to treat various physiological disorders which induce differentforms of pathologies including;

-   -   spinal degenerative pathologies, such as amyotrophic lateral        sclerosis (ALS);    -   spinal cord tumor diseases, such as spinal astrocytomas;    -   spinal inflammatory pathologies, such as multiple sclerosis,        etc. . . .

It can also be used to improve the repair and/or rehabilitationtreatments of the spinal cord and/or spinal nerve(s), for example forhemiplegia and paraplegia, including with cell transplant and/or stemcell regeneration.

The invention claimed is:
 1. An implantable ultrasound generatingtreating device to induce spinal cord treatment by emission ofultrasound waves, wherein the ultrasound generating treating device issuitable for implantation in the spinal canal and comprises: an elongatesupport member extending along an elongation path; an array of severalultrasound generating treatment transducers distributed along theelongate support member along an active portion on the elongation path;wherein the several ultrasound generating treatment transducers compriseradial transducers; wherein the ultrasound generating treatmenttransducers have an ultrasound generating resonant frequency comprisedbetween 0.5 and 4 MHz, and wherein the device has articulating portionsalong the active portion of the elongation path so that the activeportion of the implantable ultrasound generating treating device canadapt its shape to a curved elongation path; wherein the implantableultrasound generating treating device has an active portion along whichthe ultrasound generating treatment transducers are arranged, the lengthof the active portion being such that the treatment zone extendsthroughout the extension of several vertebrae of the patient.
 2. Theimplantable device according to claim 1, characterized in that theimplantable ultrasound generating treating device has an active portionalong which the ultrasound generating treatment transducers arearranged, the length of the active portion being of at least 10 cm. 3.The implantable device according to claim 2, characterized in that thecomparatively more rigid portions correspond to the location of theultrasound generating treatment transducers along the elongation path.4. The implantable device according to claim 3, characterized in thatthe elongate outer sheath tube is made of a silicone, polyurethane,and/or polytetrafluorethylene based material.
 5. The implantable deviceaccording to claim 1, characterized in that the articulating portionscomprise comparatively more flexible portions of the ultrasoundgenerating treating device in between of comparatively more rigidportions.
 6. The implantable device according to claim 1, characterizedin that the elongate outer sheath tube forms at least part of theelongate support member.
 7. The implantable device according to claim 1,characterized in that the array of several ultrasound generatingtreatment transducers are cylindrical, with an axis parallel to theelongation path.
 8. The implantable device according to claim 1,characterized in that the array of several ultrasound generatingtreatment transducers are tubular, with an axis parallel to theelongation path, and with a central aperture extending along their axis.9. The implantable device according to claim 1, characterized in thatthe elongate support member comprises an internal support memberextending though the central aperture of the ultrasound generatingtreatment transducers.
 10. The implantable device according to claim 1,characterized in that the implantable ultrasound generating treatingdevice comprises ultrasonic monitoring transducers.
 11. The implantabledevice according to claim 1, characterized in that the ultrasoundgenerating treatment transducers are connectable by an electricalconnection circuit to a generator delivering electric drive signalsdriving the generation of ultrasound from the ultrasound generatingtreatment transducers.
 12. The implantable device according to claim 11,characterized in that the electrical connection circuit of theimplantable device starts from an implantable connection receiver of theimplantable ultrasound generating treating device and delivers electricsignals to the ultrasound generating treatment transducers for drivingthe ultrasound generation of the ultrasound generating treatmenttransducers.
 13. The implantable device according to claim 12,characterized in that the implantable connection receiver is designedfor cooperation with the generator to achieve electrical connectionbetween the generator and the ultrasound generating treating device. 14.The implantable device according to claim 11, characterized in that theelectrical connection circuit of the implantable ultrasound generatingtreating device starts from a connection receiver of the implantableultrasound generating treating device, the connection receiver designedfor cooperation with a connector of the generator which comprises one orseveral transdermal needles suitable for plugging into the connectionreceiver through the patient's skin.
 15. The implantable deviceaccording to claim 1, characterized in that it comprises an implantableelectrical generator.
 16. The implantable device according to claim 15,characterized in that the implantable electrical generator is remotelycontrolled by an external controller.
 17. An apparatus to induce spinalcord treatment by emission of ultrasound waves, comprising: animplantable ultrasound generating treating device according to claim 1;an electrical generator which generates electric signals to be deliveredto the transducers of the implantable ultrasound generating treatingdevice; a controller.
 18. The apparatus according to claim 17,characterized in that the electrical generator is remotely controlled byan external controller.
 19. The apparatus according to claim 17,characterized in that the external controller comprises a treatmentcontrol module for controlling the electrical generator in view ofproviding the adequate electric drive signals to the implantableultrasound generating treating device for it to generate an ultrasoundtreatment pulsed beam, having a mean burst duration, as the mean timefrom the start of a pulse to the end of that pulse, is between 10 msec.and 100 msec., and a delay between two successive pulses is from 30msec. to 1000 msec.
 20. The apparatus according to claim 17,characterized in that the array of several ultrasound generatingtreatment transducers have an ultrasound generating resonant frequencycomprised between 0.5 and 4 MHz, and the pressure level of theultrasound treatment beam is comprised between 0.8 MPa and 3.0 MPa.